The overall goal of this AADCRC proposal is to define the role of the epithelial cell barrier in the pathogenesis of asthma and allergic disease and to use that information to prevent this type of disease. We combine expertise in airway as well as gut and skin epithelial cell biology, and we use cell and mouse models with high fidelity to directly translate our findings to humans. The AADRC therefore consists of three interrelated Projects that ask, first, how airway epithelial cells mediate effective antiviral defense under one condition but asthma under another (Project 1), second, how airway epithelial cells remodel towards an overabundance of mucous cells in post-viral and allergic asthma (Project 2), and third, how epithelial injury in the skin triggers the march from atopic dermatitis to asthma (Project 3). Each project addresses the respective question with a novel but overlapping molecular approach to mechanism and takes advantage of a breakthrough discovery to set a new scientific paradigm for the system under study. Thus, Project 1 unravels a new IFN signaling pathway that offers improved protection against viral infection and post-viral asthma and is specific to the airway epithelial cell barrier; Project 2 dissects a new pathway for autophagy proteins to support proper mucous cell function and prevent mucous cell metaplasia in the airway in a manner reminiscent of the intestinal epithelial barrier; and Project 3 defines a new TSLP production and secretion pathway that drives airway inflammation based on its expression in the skin epithelial barrier. Each Project is constructed so that the first aim will establish a basic pathogenic mechanism using cell and mouse models that are shared among projects and supported by the Cores for tissue and cell processing (Core C) and mouse models (Core D). In turn, each Project will conduct a second aim to validate and translate its findings using samples from children and adults with asthma and/or atopic dermatitis supplied by the Core for human subjects and data analysis (Core B). Sharing samples and overlapping scientific goals among projects create a synergistic program that can be coordinated by a common Administrative Core (Core A). Project and Core interactions are based on the overall principle that each Project begins with molecular hypothesis building in cell and mouse models and translates findings from these models to studies of humans with asthma and/or allergy. In each project, we aim to validate a clinically useful biomarker of the disease process and lay the groundwork for the future development of biological and/or small molecular weight compounds that might influence the process as a therapeutic strategy.